The grant is designed to uncover new secondary metabolites from higher plants wich have novel chemical structures and which have potential for clinical use as antibiotics in the treatment of infections caused by microorganisms against which current fermentation based antibiotics are unsatisfactory in some significant way. Central to this effort is the use of rational modern testing methods and we have chosen to search among the higher plants for these structurally and therapeutically novel agents. Once confirmed to be active, the most potent plant extracts are fractionated in order to isolate the active constituents in pure form. These products are then evaluated for their antimicrobial spectrum and comparative potency in vitro in comparison with established antibiotics. In vivo evaluation in infected mice is carried out on the most potent agents. The new agents uncovered are often present in small amounts so syntheses often have to be developed in order to confirm the structures, prepare enough for significant evaluation and prepare analogs to explore the relationship between structure and activity. This is necessary because there are no precedent structures to guide one in the antibiotic literature and because of the desire to improve the medicinal potential of substances whose intrinsic activity is too weak for clinical use by themselves. The diseases under attack by these methods include tuberculosis, infections due to Gram-negative bacteria, and fungal diseases. BIBLIOGRAPHIC REFERENCES: L. A. Mitscher, T. Suzuki, G. Clark and M. S. Bathala. Total Synthesis of 2,4-Dioxyquinoline Alkaloids. Heterocycles, 5, 565 (1976). L. A. Mitscher. Plant-Derived Antibiotics. Chapter in "Isolation, Separation and Purification of Antibiotics," Eds. G. Wagman and G. Weinstein, Elsevier, Amsterdam (1977), in press.